The initiation and maintenance of motivated behaviors often are characterized by a high degree of vigor,speed, persistence and work output, and organisms frequently make effort-related decisions based upon cost/benefit analyses. In addition, clinicians emphasize the importance of effort-related symptoms, such as anergia, psychomotor retardation, apathy and fatigue, in major depression and other disorders. These motivational symptoms are among the most common symptoms of depression; they can strongly interfere with activities of daily living, and can be highly resistant to treatment. While catecholamine uptake inhibitors appear to be somewhat effective drugs for treating the psychomotor/motivational symptoms of depression, clinical studies indicate that serotonin transport (SERT) inhibitors such as fluoxetine are relatively poor at treating anergia and fatigue, and in fact, can induce or exacerbate these symptoms. Our laboratory has developed behavioral tasks in rodents that assess the brain mechanisms regulating the exertion of effort and effort-related choice behavior. These tests of effort-related choice behavior allow animals to make choices between high-effort alternatives that lead to more highly valued rewards vs. low-effort alternatives that lead to less valued reward (i.e., less preferred or lower in magnitude). Recently, our laboratory has demonstrated that tests of effort-based choice behavior can be used as animal models of the effort-related motivational symptoms of depression. A number of conditions associated with depression in humans can alter effort-related choice in rats, and bias animals towards low-effort options. For example, rats treated with vesicular monoamine transport inhibitor tetrabenazine, which induces or exacerbates symptoms of depression in humans, can alter effort-related choice, reducing selection of the high effort alternative. These effects can be reversed by co-administration of putative antidepressants such as the adenosine A2A antagonist MSX-3, the established antidepressant bupropion (Wellbutrin), which inhibits catecholamine uptake, and the selective dopamine (DA) uptake blockers GBR12909 and PRX-14040. Importantly, research from our laboratory shows that SERT inhibitors, rather than reversing the effort-related effects of tetrabenazine, actually tend to exacerbate them. Furthermore, our recent studies show that the SERT inhibitor fluoxetine reduces effort expenditure and lowers extracellular DA in nucleus accumbens, which is consistent with the relatively poor effects of these drugs on motivational symptoms in depressed people. The goal of the proposed investigation is to determine if the 5-HT2C receptor mediates these effects by studying the ability of 5-HT2A and 5-HT2C antagonists, injected systemically or intracranially, to reverse the effects of fluoxetine on effort-related decision making and extracellular DA in nucleus accumbens. This research could lead to a greater understanding of the neurochemical mechanisms that underlie the regulation of effort-related aspects of motivation, and foster the development of treatments that augment the therapeutic efficacy of 5-HT uptake inhibitors.